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  2. Prevention of ketamine-induced working memory impairments by AMPA potentiators in a nonhuman primate model of cognitive dysfunction

Prevention of ketamine-induced working memory impairments by AMPA potentiators in a nonhuman primate model of cognitive dysfunction

  • Behav Brain Res. 2010 Sep 1;212(1):41-8. doi: 10.1016/j.bbr.2010.03.039.
Brooke M Roberts 1 Daniel E Holden Christopher L Shaffer Patricia A Seymour Frank S Menniti Christopher J Schmidt Graham V Williams Stacy A Castner
Affiliations

Affiliation

  • 1 Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, United States; VA Connecticut Healthcare System, West Haven, CT 06519, United States.
Abstract

Working memory impairments are a core aspect of schizophrenia, yet current medicines do not address such cognitive dysfunction. We have developed a model of these working memory deficits by acutely disrupting glutamatergic synaptic transmission by administration of the N-methyl-d-aspartate (NMDA) antagonist ketamine in the nonhuman primate. The current studies evaluated the effect of positive allosteric modulators ("potentiators") of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors on the working memory and behavioral effects of ketamine. AMPA receptors mediate fast excitatory synaptic transmission throughout the brain and play a critical role in the activity-dependent regulation of NMDA receptors. We find that positive modulation of AMPA receptors with LY451646 (0.1-1.0mg/kg, SC) and structurally distinct PF-4778574 (0.01mg/kg, SC) robustly ameliorates ketamine-induced working memory impairments without altering behavioral effects of acute ketamine we consider related to positive- and negative-like symptoms. These results support AMPA receptor potentiators as a potential adjunctive treatment for cognitive impairment associated with schizophrenia (CIAS).

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